Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Molecular Biology

The mitochondrial quality control system: a new target for exercise therapeutic intervention in the treatment of brain insulin resistance-induced neurodegeneration in obesity

Subjects

Abstract

Obesity is a major global health concern because of its strong association with metabolic and neurodegenerative diseases such as diabetes, dementia, and Alzheimer’s disease. Unfortunately, brain insulin resistance in obesity is likely to lead to neuroplasticity deficits. Since the evidence shows that insulin resistance in brain regions abundant in insulin receptors significantly alters mitochondrial efficiency and function, strategies targeting the mitochondrial quality control system may be of therapeutic and practical value in obesity-induced cognitive decline. Exercise is considered as a powerful stimulant of mitochondria that improves insulin sensitivity and enhances neuroplasticity. It has great potential as a non-pharmacological intervention against the onset and progression of obesity associated neurodegeneration. Here, we integrate the current knowledge of the mechanisms of neurodegenration in obesity and focus on brain insulin resistance to explain the relationship between the impairment of neuronal plasticity and mitochondrial dysfunction. This knowledge was synthesised to explore the exercise paradigm as a feasible intervention for obese neurodegenration in terms of improving brain insulin signals and regulating the mitochondrial quality control system.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Insulin and insulin signalling in the brain of obesity.
Fig. 2: The links among insulin resistance, mitochondria, and neuronal plasticity in obese brain.
Fig. 3: Graphical summary of the mitochondrial quality control system.
Fig. 4: Exercise may remedy insulin resistance in the obese brain and target brain mitochondrial quality control system to repair mitochondrial dysfunction.

Similar content being viewed by others

References

  1. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384:766–81.

    Article  PubMed  PubMed Central  Google Scholar 

  2. N.C.D.R.F. Collaboration, Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016. a pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults. Lancet. 2017;390:2627–42.

    Google Scholar 

  3. Obri A, Serra D, Herrero L, Mera P. The role of epigenetics in the development of obesity. Biochem Pharmacol. 2020;177:113973.

    Article  CAS  PubMed  Google Scholar 

  4. Ali HI, Attlee A, Alhebshi S, Elmi F, Al Dhaheri AS, Stojanovska L, et al. Feasibility study of a newly developed technology-mediated lifestyle intervention for overweight and obese young adults. Nutrients. 2021;13:2547.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Dye L, Boyle NB, Champ C, Lawton C. The relationship between obesity and cognitive health and decline. Proc Nutr Soc. 2017;76:443–54.

    Article  PubMed  Google Scholar 

  6. Kullmann S, Heni M, Hallschmid M, Fritsche A, Preissl H, Haring HU. Brain insulin resistance at the crossroads of metabolic and cognitive disorders in humans. Physiolog Reviews. 2016;96:1169–209.

    Article  CAS  Google Scholar 

  7. Morys F, Potvin O, Zeighami Y, Vogel J, Lamontagne-Caron R, Duchesne S, et al. Obesity-associated neurodegeneration pattern mimics Alzheimer’s disease in an observational Cohort study. J Alzheimer’s Dis. 2023;91:1059–71.

    Article  CAS  Google Scholar 

  8. Guo S. Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms. J Endocrinol. 2014;220:T1–T23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kothari V, Luo Y, Tornabene T, O’Neill AM, Greene MW, Geetha T, et al. High fat diet induces brain insulin resistance and cognitive impairment in mice. Biochim Biophys Acta Mol Basis Dis. 2017;1863:499–508.

    Article  CAS  PubMed  Google Scholar 

  10. Arvanitakis Z, Capuano AW, Wang HY, Schneider JA, Kapasi A, Bennett DA, et al. Brain insulin signaling and cerebrovascular disease in human postmortem brain. Acta Neuropathol Commun. 2021;9:71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ruegsegger GN, Vanderboom PM, Dasari S, Klaus KA, Kabiraj P, McCarthy CB, et al. Exercise and metformin counteract altered mitochondrial function in the insulin-resistant brain. JCI insight. 2019;4:e130681.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ruegsegger GN, Manjunatha S, Summer P, Gopala S, Zabeilski P, Dasari S, et al. Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes. FASEB J: Off Publ Fed Am Soc Exp Biol. 2019;33:4458–72.

    Article  CAS  Google Scholar 

  13. Kleinridders A, Cai W, Cappellucci L, Ghazarian A, Collins WR, Vienberg SG, et al. Insulin resistance in brain alters dopamine turnover and causes behavioral disorders. Proc Natl Acad Sci USA. 2015;112:3463–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lahera V, de Las Heras N, Lopez-Farre A, Manucha W, Ferder L. Role of mitochondrial dysfunction in hypertension and obesity. Curr Hyper Rep. 2017;19:11.

    Article  Google Scholar 

  15. Cai Q, Tammineni P. Alterations in mitochondrial quality control in Alzheimer’s disease. Front Cell Neurosci. 2016;10:24.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Markham A, Bains R, Franklin P, Spedding M. Changes in mitochondrial function are pivotal in neurodegenerative and psychiatric disorders: how important is BDNF? Br J Pharmacol. 2014;171:2206–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Richter M, Vidovic N, Honrath B, Mahavadi P, Dodel R, Dolga AM, et al. Activation of SK2 channels preserves ER Ca(2)(+) homeostasis and protects against ER stress-induced cell death. Cell Death Differ. 2016;23:814–27.

    Article  CAS  PubMed  Google Scholar 

  18. Xu X, Fu Z, Le W. Exercise and Parkinson’s disease. Int Rev Neurobiol. 2019;147:45–74.

    Article  CAS  PubMed  Google Scholar 

  19. Cassilhas RC, Tufik S, de Mello MT. Physical exercise, neuroplasticity, spatial learning and memory. Cell Mol Life Sci: CMLS. 2016;73:975–83.

    Article  CAS  PubMed  Google Scholar 

  20. Bertram S, Brixius K, Brinkmann C. Exercise for the diabetic brain: how physical training may help prevent dementia and Alzheimer’s disease in T2DM patients. Endocrine. 2016;53:350–63.

    Article  CAS  PubMed  Google Scholar 

  21. Jang Y, Kwon I, Cosio-Lima L, Wirth C, Vinci DM, Lee Y. Endurance exercise prevents metabolic distress-induced senescence in the hippocampus. Med Sci Sports Exerc. 2019;51:2012–24.

    Article  CAS  PubMed  Google Scholar 

  22. Cai M, Wang H, Li JJ, Zhang YL, Xin L, Li F, et al. The signaling mechanisms of hippocampal endoplasmic reticulum stress affecting neuronal plasticity-related protein levels in high fat diet-induced obese rats and the regulation of aerobic exercise. Brain Behav Immun. 2016;57:347–59.

    Article  CAS  PubMed  Google Scholar 

  23. Chieffi S, Messina G, Villano I, Messina A, Valenzano A, Moscatelli F, et al. Neuroprotective effects of physical activity: evidence from human and animal studies. Front Neurol. 2017;8:188.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Bernardo TC, Marques-Aleixo I, Beleza J, Oliveira PJ, Ascensao A, Magalhaes J. Physical exercise and brain mitochondrial fitness: the possible role against Alzheimer’s disease. Brain Pathol. 2016;26:648–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Raefsky SM, Mattson MP. Adaptive responses of neuronal mitochondria to bioenergetic challenges: Roles in neuroplasticity and disease resistance. Free Rad Biol Med. 2017;102:203–16.

    Article  CAS  PubMed  Google Scholar 

  26. Hood DA, Memme JM, Oliveira AN, Triolo M. Maintenance of skeletal muscle mitochondria in health, exercise, and aging. Annu Rev Physiol. 2019;81:19–41.

    Article  CAS  PubMed  Google Scholar 

  27. Huertas JR, Casuso RA, Agustin PH, Cogliati S. Stay fit, stay young: mitochondria in movement: the role of exercise in the new mitochondrial paradigm. Oxid Med Cell Longev. 2019;7058350..

  28. Kullmann S, Schweizer F, Veit R, Fritsche A, Preissl H. Compromised white matter integrity in obesity. Obes Rev: Off J Int Assoc Study Obes. 2015;16:273–81.

    Article  CAS  Google Scholar 

  29. van Bloemendaal L, Ijzerman RG, Ten Kulve JS, Barkhof F, Diamant M, Veltman DJ, et al. Alterations in white matter volume and integrity in obesity and Type 2 diabetes. Metab Brain Dis. 2016;31:621–9.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Lampe L, Zhang R, Beyer F, Huhn S, Kharabian Masouleh S, Preusser S, et al. Visceral obesity relates to deep white matter hyperintensities via inflammation. Ann Neurol. 2019;85:194–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ronan L, Alexander-Bloch AF, Wagstyl K, Farooqi S, Brayne C, Tyler LK, et al. Obesity associated with increased brain age from midlife. Neurobiol Aging. 2016;47:63–70.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kalupahana NS, Moustaid-Moussa N, Claycombe KJ. Immunity as a link between obesity and insulin resistance. Mol Aspects Med. 2012;33:26–34.

    Article  CAS  PubMed  Google Scholar 

  33. Kellar D, Craft S. Brain insulin resistance in Alzheimer’s disease and related disorders: mechanisms and therapeutic approaches. Lancet Neurol. 2020;19:758–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Boden G. Effects of free fatty acids (FFA) on glucose metabolism: significance for insulin resistance and type 2 diabetes. Exp Clin Endocrinol Diabetes. 2003;111:121–4.

    Article  CAS  PubMed  Google Scholar 

  35. Ahmed B, Sultana R, Greene MW. Adipose tissue and insulin resistance in obese. Biomed Pharmacother. 2021;137:111315.

    Article  CAS  PubMed  Google Scholar 

  36. Mirabelli M, Chiefari E, Arcidiacono B, Corigliano DM, Brunetti FS, Maggisano V, et al. Mediterranean diet nutrients to turn the tide against insulin resistance and related diseases. Nutrients. 2020;12:1066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cai Z, Huang Y, He B. New Insights into Adipose Tissue Macrophages in Obesity and Insulin Resistance. Cells. 2022;11:1424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rohm TV, Meier DT, Olefsky JM, Donath MY. Inflammation in obesity, diabetes, and related disorders. Immunity. 2022;55:31–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Milstein JL, Ferris HA. The brain as an insulin-sensitive metabolic organ. Mol Metab. 2021;52:101234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kleinridders A, Ferris HA, Cai W, Kahn CR. Insulin action in brain regulates systemic metabolism and brain function. Diabetes. 2014;63:2232–43.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Grillo CA, Woodruff JL, Macht VA, Reagan LP. Insulin resistance and hippocampal dysfunction: disentangling peripheral and brain causes from consequences. Exp Neurol. 2019;318:71–77.

    Article  CAS  PubMed  Google Scholar 

  42. Banks WA, Owen JB, Erickson MA. Insulin in the brain: there and back again. Pharmacol Ther. 2012;136:82–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A. Insulin in the brain: sources, localization and functions. Mol Neurobiol. 2013;47:145–71.

    Article  CAS  PubMed  Google Scholar 

  44. Havrankova J, Roth J, Brownstein M. Insulin receptors are widely distributed in the central nervous system of the rat. Nature. 1978;272:827–9.

    Article  CAS  PubMed  Google Scholar 

  45. Agrawal R, Reno CM, Sharma S, Christensen C, Huang Y, Fisher SJ. Insulin action in the brain regulates both central and peripheral functions. Am J Physiol Endocrinol Metab. 2021;321:E156–E163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Craft S, Watson GS. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol. 2004;3:169–78.

    Article  CAS  PubMed  Google Scholar 

  47. Sharma VK, Singh TG. Insulin resistance and bioenergetic manifestations: Targets and approaches in Alzheimer’s disease. Life Sci. 2020;262:118401.

    Article  CAS  PubMed  Google Scholar 

  48. Begg DP. Insulin transport into the brain and cerebrospinal fluid. Vitam Horm. 2015;98:229–48.

    Article  CAS  PubMed  Google Scholar 

  49. Kern W, Benedict C, Schultes B, Plohr F, Moser A, Born J, et al. Low cerebrospinal fluid insulin levels in obese humans. Diabetologia. 2006;49:2790–2.

    Article  CAS  PubMed  Google Scholar 

  50. Yoo DY, Yim HS, Jung HY, Nam SM, Kim JW, Choi JH, et al. Chronic type 2 diabetes reduces the integrity of the blood-brain barrier by reducing tight junction proteins in the hippocampus. J Veterinary Med Sci. 2016;78:957–62.

    Article  CAS  Google Scholar 

  51. Sedzikowska A, Szablewski L. Insulin and insulin resistance in Alzheimer’s disease. Int J Mol Sci. 2021;22:9987.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Csajbok EA, Tamas G. Cerebral cortex: a target and source of insulin? Diabetologia. 2016;59:1609–15.

    Article  CAS  PubMed  Google Scholar 

  53. Kuwabara T, Kagalwala MN, Onuma Y, Ito Y, Warashina M, Terashima K, et al. Insulin biosynthesis in neuronal progenitors derived from adult hippocampus and the olfactory bulb. EMBO Mol Med. 2011;3:742–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Dorn A, Rinne A, Bernstein HG, Hahn HJ, Ziegler M. Insulin and C-peptide in human brain neurons (insulin/C-peptide/brain peptides/immunohistochemistry/radioimmunoassay). J Hirnforsch. 1983;24:495–9.

    CAS  PubMed  Google Scholar 

  55. Birch NP, Christie DL, Renwick AG. Proinsulin-like material in mouse foetal brain cell cultures. FEBS Lett. 1984;168:299–302.

    Article  CAS  PubMed  Google Scholar 

  56. Devaskar SU, Giddings SJ, Rajakumar PA, Carnaghi LR, Menon RK, Zahm DS. Insulin gene expression and insulin synthesis in mammalian neuronal cells. J Biolog Chem. 1994;269:8445–54.

    Article  CAS  Google Scholar 

  57. Molnar G, Farago N, Kocsis AK, Rozsa M, Lovas S, Boldog E, et al. GABAergic neurogliaform cells represent local sources of insulin in the cerebral cortex. J Neurosci: Off J Soc Neurosci. 2014;34:1133–7.

    Article  CAS  Google Scholar 

  58. Havrankova J, Brownstein M, Roth J. Insulin and insulin receptors in rodent brain. Diabetologia. 1981;20:268–73.

    Article  CAS  PubMed  Google Scholar 

  59. Pomytkin I, Pinelis V. Brain insulin resistance: focus on insulin receptor-mitochondria interactions. Life. 2021;11:262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Unger J, McNeill TH, Moxley RT 3rd, White M, Moss A, Livingston JN. Distribution of insulin receptor-like immunoreactivity in the rat forebrain. Neuroscience. 1989;31:143–57.

    Article  CAS  PubMed  Google Scholar 

  61. Saltiel AR. Insulin signaling in health and disease. J Clin Invest. 2021;131:e142241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Beddows CA, Dodd GT. Insulin on the brain: the role of central insulin signalling in energy and glucose homeostasis. J Neuroendocrinol. 2021;33:e12947.

    Article  CAS  PubMed  Google Scholar 

  63. Zhao N, Liu CC, Van Ingelgom AJ, Martens YA, Linares C, Knight JA, et al. Apolipoprotein E4 impairs neuronal insulin signaling by trapping insulin receptor in the endosomes. Neuron. 2017;96:115–29.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Arnold SE, Arvanitakis Z, Macauley-Rambach SL, Koenig AM, Wang HY, Ahima RS, et al. Brain insulin resistance in Type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol. 2018;14:168–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Tschritter O, Preissl H, Hennige AM, Stumvoll M, Porubska K, Frost R, et al. The cerebrocortical response to hyperinsulinemia is reduced in overweight humans: a magnetoencephalographic study. Proc Natl Acad Sci USA. 2006;103:12103–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wang D, Yan J, Chen J, Wu W, Zhu X, Wang Y. Naringin improves neuronal insulin signaling, brain mitochondrial function, and cognitive function in high-fat diet-induced obese mice. Cell Mol Neurobiol. 2015;35:1061–71.

    Article  CAS  PubMed  Google Scholar 

  67. Chua LM, Lim ML, Chong PR, Hu ZP, Cheung NS, Wong BS. Impaired neuronal insulin signaling precedes Abeta42 accumulation in female AbetaPPsw/PS1DeltaE9 mice. J Alzheimer’s Dis. 2012;29:783–91.

    Article  CAS  Google Scholar 

  68. Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D, et al. Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci USA. 2004;101:3100–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Soto M, Cai W, Konishi M, Kahn CR. Insulin signaling in the hippocampus and amygdala regulates metabolism and neurobehavior. Proc Natl Acad Sci USA. 2019;116:6379–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Grillo CA, Piroli GG, Lawrence RC, Wrighten SA, Green AJ, Wilson SP, et al. Hippocampal insulin resistance impairs spatial learning and synaptic plasticity. Diabetes. 2015;64:3927–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. McNay EC, Ong CT, McCrimmon RJ, Cresswell J, Bogan JS, Sherwin RS. Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol Learn Mem. 2010;93:546–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Schechter R, Yanovitch T, Abboud M, Johnson G 3rd, Gaskins J. Effects of brain endogenous insulin on neurofilament and MAPK in fetal rat neuron cell cultures. Brain Res. 1998;808:270–8.

    Article  CAS  PubMed  Google Scholar 

  73. Walker KA, Chawla S, Nogueras-Ortiz C, Coresh J, Sharrett AR, Wong DF, et al. Neuronal insulin signaling and brain structure in nondemented older adults: the Atherosclerosis Risk in communities study. Neurobiol Aging. 2021;97:65–72.

    Article  CAS  PubMed  Google Scholar 

  74. Recio-Pinto E, Ishii DN. Effects of insulin, insulin-like growth factor-II and nerve growth factor on neurite outgrowth in cultured human neuroblastoma cells. Brain Res. 1984;302:323–34.

    Article  CAS  PubMed  Google Scholar 

  75. Schechter R, Abboud M, Johnson G. Brain endogenous insulin effects on neurite growth within fetal rat neuron cell cultures. Brain Res Dev Brain Res. 1999;116:159–67.

    Article  CAS  PubMed  Google Scholar 

  76. Park CR, Seeley RJ, Craft S, Woods SC. Intracerebroventricular insulin enhances memory in a passive-avoidance task. Physiol Behav. 2000;68:509–14.

    Article  CAS  PubMed  Google Scholar 

  77. Haj-ali V, Mohaddes G, Babri SH. Intracerebroventricular insulin improves spatial learning and memory in male Wistar rats. Behav Neurosci. 2009;123:1309–14.

    Article  CAS  PubMed  Google Scholar 

  78. Babri S, Badie HG, Khamenei S, Seyedlar MO. Intrahippocampal insulin improves memory in a passive-avoidance task in male wistar rats. Brain Cogn. 2007;64:86–91.

    Article  PubMed  Google Scholar 

  79. Moosavi M, Naghdi N, Maghsoudi N, Zahedi Asl S. The effect of intrahippocampal insulin microinjection on spatial learning and memory. Horm Behav. 2006;50:748–52.

    Article  CAS  PubMed  Google Scholar 

  80. Moosavi M, Naghdi N, Choopani S. Intra CA1 insulin microinjection improves memory consolidation and retrieval. Peptides. 2007;28:1029–34.

    Article  CAS  PubMed  Google Scholar 

  81. Moosavi M, Naghdi N, Maghsoudi N, Zahedi Asl S. Insulin protects against stress-induced impairments in water maze performance. Behaviour Brain Res. 2007;176:230–6.

    Article  CAS  Google Scholar 

  82. Fan LW, Carter K, Bhatt A, Pang Y. Rapid transport of insulin to the brain following intranasal administration in rats. Neural Regen Res. 2019;14:1046–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Fehm HL, Perras B, Smolnik R, Kern W, Born J. Manipulating neuropeptidergic pathways in humans: a novel approach to neuropharmacology? Eur J Pharmacol. 2000;405:43–54.

    Article  CAS  PubMed  Google Scholar 

  84. Pang Y, Lin S, Wright C, Shen J, Carter K, Bhatt A, et al. Intranasal insulin protects against substantia nigra dopaminergic neuronal loss and alleviates motor deficits induced by 6-OHDA in rats. Neuroscience. 2016;318:157–65.

    Article  CAS  PubMed  Google Scholar 

  85. Mamik MK, Asahchop EL, Chan WF, Zhu Y, Branton WG, McKenzie BA, et al. Insulin treatment prevents neuroinflammation and neuronal injury with restored neurobehavioral function in models of HIV/AIDS neurodegeneration. J Neurosci: Off J Soc Neurosci. 2016;36:10683–95.

    Article  CAS  Google Scholar 

  86. Reger MA, Watson GS, Frey WH 2nd, Baker LD, Cholerton B, Keeling ML, et al. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging. 2006;27:451–8.

    Article  CAS  PubMed  Google Scholar 

  87. Reger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA, et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimer’s Dis. 2008;13:323–31.

    Article  CAS  Google Scholar 

  88. Brunner YF, Kofoet A, Benedict C, Freiherr J. Central insulin administration improves odor-cued reactivation of spatial memory in young men. J Clin Endocrinol Metab. 2015;100:212–9.

    Article  PubMed  Google Scholar 

  89. Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004;29:1326–34.

    Article  CAS  PubMed  Google Scholar 

  90. Benedict C, Hallschmid M, Schmitz K, Schultes B, Ratter F, Fehm HL, et al. Intranasal insulin improves memory in humans: superiority of insulin aspart. Neuropsychopharmacology. 2007;32:239–43.

    Article  CAS  PubMed  Google Scholar 

  91. Hallschmid M, Benedict C, Schultes B, Born J, Kern W. Obese men respond to cognitive but not to catabolic brain insulin signaling. Int J Obes. 2008;32:275–82.

    Article  CAS  Google Scholar 

  92. Craft S, Raman R, Chow TW, Rafii MS, Sun CK, Rissman RA, et al. Safety, efficacy, and feasibility of intranasal insulin for the treatment of mild cognitive impairment and alzheimer disease dementia: a randomized clinical trial. JAMA Neurol. 2020;77:1099–109.

    Article  PubMed  Google Scholar 

  93. Cardoso S, Seiça RM, Moreira PI. Mitochondria as a target for neuroprotection: implications for Alzheimer´s disease. Expert Rev Neurother. 2016;17:77–91.

    Article  PubMed  Google Scholar 

  94. Pipatpiboon N, Pratchayasakul W, Chattipakorn N, Chattipakorn SC. PPARgamma agonist improves neuronal insulin receptor function in hippocampus and brain mitochondria function in rats with insulin resistance induced by long term high-fat diets. Endocrinology. 2012;153:329–38.

    Article  CAS  PubMed  Google Scholar 

  95. Pratchayasakul W, Sa-nguanmoo P, Sivasinprasasn S, Pintana H, Tawinvisan R, Sripetchwandee J, et al. Obesity accelerates cognitive decline by aggravating mitochondrial dysfunction, insulin resistance and synaptic dysfunction under estrogen-deprived conditions. Horm Behav. 2015;72:68–77.

    Article  CAS  PubMed  Google Scholar 

  96. Pintana H, Apaijai N, Chattipakorn N, Chattipakorn SC. DPP-4 inhibitors improve cognition and brain mitochondrial function of insulin-resistant rats. J Endocrinol. 2013;218:1–11.

    Article  CAS  PubMed  Google Scholar 

  97. Sa-Nguanmoo P, Tanajak P, Kerdphoo S, Satjaritanun P, Wang X, Liang G, et al. FGF21 improves cognition by restored synaptic plasticity, dendritic spine density, brain mitochondrial function and cell apoptosis in obese-insulin resistant male rats. Horm Behav. 2016;85:86–95.

    Article  CAS  PubMed  Google Scholar 

  98. Pintana H, Sripetchwandee J, Supakul L, Apaijai N, Chattipakorn N, Chattipakorn S. Garlic extract attenuates brain mitochondrial dysfunction and cognitive deficit in obese-insulin resistant rats. Appl Physiol Nutr Metab. 2014;39:1373–9.

    Article  CAS  PubMed  Google Scholar 

  99. Schell M, Wardelmann K, Kleinridders A. Untangling the effect of insulin action on brain mitochondria and metabolism. J Neuroendocrinol. 2021;33:e12932.

    Article  CAS  PubMed  Google Scholar 

  100. Cai W, Xue C, Sakaguchi M, Konishi M, Shirazian A, Ferris HA, et al. Insulin regulates astrocyte gliotransmission and modulates behavior. J Clin Investig. 2018;128:2914–26.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Garcia-Caceres C, Quarta C, Varela L, Gao Y, Gruber T, Legutko B, et al. Astrocytic insulin signaling couples brain glucose uptake with nutrient availability. Cell. 2016;166:867–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Filippi BM, Abraham MA, Silva PN, Rasti M, LaPierre MP, Bauer PV, et al. Dynamin-related protein 1-dependent mitochondrial fission changes in the dorsal vagal complex regulate insulin action. Cell Rep. 2017;18:2301–9.

    Article  CAS  PubMed  Google Scholar 

  103. Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature. 2007;450:736–40.

    Article  CAS  PubMed  Google Scholar 

  104. Ruegsegger GN, Creo AL, Cortes TM, Dasari S, Nair KS. Altered mitochondrial function in insulin-deficient and insulin-resistant states. J Clin Invest. 2018;128:3671–81.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Rolfe DF, Brown GC. Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol Rev. 1997;77:731–58.

    Article  CAS  PubMed  Google Scholar 

  106. Magistretti PJ, Allaman I. Lactate in the brain: from metabolic end-product to signalling molecule. Nat Rev Neurosci. 2018;19:235–49.

    Article  CAS  PubMed  Google Scholar 

  107. Magistretti PJ, Allaman I. A cellular perspective on brain energy metabolism and functional imaging. Neuron. 2015;86:883–901.

    Article  CAS  PubMed  Google Scholar 

  108. Schon EA, Przedborski S. Mitochondria: the next (neurode)generation. Neuron. 2011;70:1033–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Tatsuta T, Langer T. Quality control of mitochondria: protection against neurodegeneration and ageing. EMBO J. 2008;27:306–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Meyer JN, Leuthner TC, Luz AL. Mitochondrial fusion, fission, and mitochondrial toxicity. Toxicology. 2017;391:42–53.

    Article  CAS  PubMed  Google Scholar 

  111. Hollenbeck PJ, Saxton WM. The axonal transport of mitochondria. J Cell Sci. 2005;118:5411–9.

    Article  CAS  PubMed  Google Scholar 

  112. Chamberlain KA, Sheng ZH. Mechanisms for the maintenance and regulation of axonal energy supply. J Neurosci Res. 2019;97:897–913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Cardoso S, Seica RM, Moreira PI. Mitochondria as a target for neuroprotection: implications for Alzheimer s disease. Expert Rev Neurother. 2017;17:77–91.

    Article  CAS  PubMed  Google Scholar 

  114. Zhu J, Wang KZ, Chu CT. After the banquet: mitochondrial biogenesis, mitophagy, and cell survival. Autophagy. 2013;9:1663–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Andreux PA, Houtkooper RH, Auwerx J. Pharmacological approaches to restore mitochondrial function. Nat Rev Drug Discov. 2013;12:465–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zhang F, Zhang L, Qi Y, Xu H. Mitochondrial cAMP signaling. Cell Mol Life Sci: CMLS. 2016;73:4577–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Liang Q, Kobayashi S. Mitochondrial quality control in the diabetic heart. J Mol Cell Cardiol. 2016;95:57–69.

    Article  CAS  PubMed  Google Scholar 

  118. Jiao Z, Wu Y, Qu S. Fenpropathrin induces degeneration of dopaminergic neurons via disruption of the mitochondrial quality control system. Cell Death Discov. 2020;6:78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. v.d. Bliek AM, Shen Q, Kawajiri S. Mechanisms of mitochondrial fission and fusion. Cold Spring Harb Perspect Biol. 2013;5:a011072.

    Google Scholar 

  120. Song J, Li Q, Ke L, Liang J, Jiao W, Pan H, et al. Qiangji Jianli decoction alleviates hydrogen peroxide-induced mitochondrial dysfunction via regulating mitochondrial dynamics and biogenesis in L6 myoblasts. Oxid Med Cell Longev. 2021;6660616..

  121. Wai T, Langer T. Mitochondrial dynamics and metabolic regulation. Trends Endocrinol Metab: TEM. 2016;27:105–17.

    Article  CAS  PubMed  Google Scholar 

  122. Luo X, Cai S, Li Y, Li G, Cao Y, Ai C, et al. Drp-1 as potential therapeutic target for lipopolysaccharide-induced vascular hyperpermeability. Oxid Med Cell Longev. 2020;5820245..

  123. Weids AJ, Grant CM. The yeast peroxiredoxin Tsa1 protects against protein-aggregate-induced oxidative stress. J Cell Sci. 2014;127:1327–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Chen CC, Li HY, Leu YL, Chen YJ, Wang CJ, Wang SH. Corylin inhibits vascular cell inflammation, proliferation and migration and reduces atherosclerosis in ApoE-deficient mice. Antioxidants (Basel). 2020;9:275.

    Article  CAS  PubMed  Google Scholar 

  125. Loson OC, Song Z, Chen H, Chan DC. Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell. 2013;24:659–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Zhang X, Shan P, Homer R, Zhang Y, Petrache I, Mannam P, et al. Cathepsin E promotes pulmonary emphysema via mitochondrial fission. Am J Pathol. 2014;184:2730–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Rovira-Llopis S, Banuls C, Diaz-Morales N, Hernandez-Mijares A, Rocha M, Victor VM. Mitochondrial dynamics in Type 2 diabetes: pathophysiological implications. Redox Biology. 2017;11:637–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Xian H, Liou YC. Functions of outer mitochondrial membrane proteins: mediating the crosstalk between mitochondrial dynamics and mitophagy. Cell Death Differ. 2021;28:827–42.

    Article  PubMed  Google Scholar 

  129. Hartmann B, Wai T, Hu H, MacVicar T, Musante L, Fischer-Zirnsak B, et al. Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation. Elife. 2016;5:e16078.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Pang Y, Qin M, Hu P, Ji K, Xiao R, Sun N, et al. Resveratrol protects retinal ganglion cells against ischemia induced damage by increasing Opa1 expression. Int J Mol Med. 2020;46:1707–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell. 2004;15:5001–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Okamoto K, Shaw JM. Mitochondrial morphology and dynamics in yeast and multicellular eukaryotes. Ann Rev Genet. 2005;39:503–36.

    Article  CAS  PubMed  Google Scholar 

  133. Yoo SM, Jung YK. A molecular approach to mitophagy and mitochondrial dynamics. Mol Cells. 2018;41:18–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Twig G, Hyde B, Shirihai OS. Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. Biochim et Biophys Acta. 2008;1777:1092–7.

    Article  CAS  Google Scholar 

  135. Strom J, Xu B, Tian X, Chen QM. Nrf2 protects mitochondrial decay by oxidative stress. FASEB J. 2016;30:66–80.

    Article  CAS  PubMed  Google Scholar 

  136. Zhou Y, Long Q, Wu H, Li W, Qi J, Wu Y, et al. Topology-dependent, bifurcated mitochondrial quality control under starvation. Autophagy. 2020;16:562–74.

    Article  PubMed  Google Scholar 

  137. Westermann B. Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol. 2010;11:872–84.

    Article  CAS  PubMed  Google Scholar 

  138. Youle RJ, van der Bliek AM. Mitochondrial fission, fusion, and stress. Science. 2012;337:1062–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Ishihara N, Nomura M, Jofuku A, Kato H, Suzuki SO, Masuda K, et al. Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat Cell Biol. 2009;11:958–66.

    Article  CAS  PubMed  Google Scholar 

  140. Bertholet AM, Delerue T, Millet AM, Moulis MF, David C, Daloyau M, et al. Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity. Neurobiol Dis. 2016;90:3–19.

    Article  CAS  PubMed  Google Scholar 

  141. Wang X, Su B, Lee HG, Li X, Perry G, Smith MA, et al. Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J. Neurosci. 2009;29:9090–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Lee S, Sterky FH, Mourier A, Terzioglu M, Cullheim S, Olson L, et al. Mitofusin 2 is necessary for striatal axonal projections of midbrain dopamine neurons. Hum Mol Genet. 2012;21:4827–35.

    Article  CAS  PubMed  Google Scholar 

  143. Bertholet AM, Millet ALME, Guillermin O, Daloyau MN, Davezac NL, Miquel M-C, et al. OPA1 loss of function affects in vitro neuronal maturation. Brain. 2013;136:1518–33.

    Article  PubMed  Google Scholar 

  144. Shields LY, Kim H, Zhu L, Haddad D, Berthet A, Pathak D, et al. Dynamin-related protein 1 is required for normal mitochondrial bioenergetic and synaptic function in CA1 hippocampal neurons. Cell Death Dis. 2015;6:e1725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Ye S, Zhou T, Cheng K, Chen M, Wang Y, Jiang Y, et al. Carboxylic acid fullerene (C60) derivatives attenuated neuroinflammatory responses by modulating mitochondrial dynamics. Nanoscale Res Lett. 2015;10:953.

    Article  PubMed  Google Scholar 

  146. Koo JH, Kang EB. Effects of treadmill exercise on the regulatory mechanisms of mitochondrial dynamics and oxidative stress in the brains of high-fat diet fed rats. J Exerc Nutrition Biochem. 2019;23:28–35.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Maneechote C, Chunchai T, Apaijai N, Chattipakorn N, Chattipakorn SC. Pharmacological targeting of mitochondrial fission and fusion alleviates cognitive impairment and brain pathologies in pre-diabetic rats. Mol Neurobiol. 2022;59:3690–702.

    Article  CAS  PubMed  Google Scholar 

  148. Zhu X, Wu S, Zeng W, Chen X, Zheng T, Ren J, et al. Protective effects of rapamycin on trabecular meshwork cells in glucocorticoid-induced glaucoma mice. Front Pharmacol. 2020;11:1006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Chu CT. A pivotal role for PINK1 and autophagy in mitochondrial quality control: implications for Parkinson disease. Hum Mol Genet. 2010;19:R28–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 2007;8:741–52.

    Article  CAS  PubMed  Google Scholar 

  151. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 2010;8:e1000298.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Ordureau A, Heo JM, Duda DM, Paulo JA, Olszewski JL, Yanishevski D, et al. Defining roles of PARKIN and ubiquitin phosphorylation by PINK1 in mitochondrial quality control using a ubiquitin replacement strategy. Proc Natl Acad Sci USA. 2015;112:6637–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Okatsu K, Saisho K, Shimanuki M, Nakada K, Shitara H, Sou YS, et al. p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria. Genes Cells: Devoted Mol Cell Mech. 2010;15:887–900.

    Article  CAS  Google Scholar 

  154. Lee JY, Nagano Y, Taylor JP, Lim KL, Yao TP. Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy. J Cell Biol. 2010;189:671–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Geisler S, Holmstrom KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol. 2010;12:119–31.

    Article  CAS  PubMed  Google Scholar 

  156. Noda S, Sato S, Fukuda T, Tada N, Uchiyama Y, Tanaka K, et al. Loss of Parkin contributes to mitochondrial turnover and dopaminergic neuronal loss in aged mice. Neurobiol Dis. 2020;136:104717.

    Article  CAS  PubMed  Google Scholar 

  157. Yasuda T, Hayakawa H, Nihira T, Ren YR, Nakata Y, Nagai M, et al. Parkin-mediated protection of dopaminergic neurons in a chronic MPTP-minipump mouse model of Parkinson disease. J Neuropathol Exp Neurol. 2011;70:686–97.

    Article  PubMed  Google Scholar 

  158. Wood-Kaczmar A, Gandhi S, Yao Z, Abramov AY, Miljan EA, Keen G, et al. PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons. PloS ONE. 2008;3:e2455.

    Article  PubMed  PubMed Central  Google Scholar 

  159. Zheng L, Bernard-Marissal N, Moullan N, D’Amico D, Auwerx J, Moore DJ, et al. Parkin functionally interacts with PGC-1alpha to preserve mitochondria and protect dopaminergic neurons. Hum Mol Genet. 2017;26:582–98.

    CAS  PubMed  Google Scholar 

  160. Sukhorukov V, Voronkov D, Baranich T, Mudzhiri N, Magnaeva A, Illarioshkin S. Impaired mitophagy in neurons and glial cells during aging and age-related disorders. Int J Mol Sci. 2021;22:10251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Sun N, Yun J, Liu J, Malide D, Liu C, Rovira II, et al. Measuring in vivo mitophagy. Mol Cell. 2015;60:685–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Han S, Zhang M, Jeong YY, Margolis DJ, Cai Q. The role of mitophagy in the regulation of mitochondrial energetic status in neurons. Autophagy. 2021;17:4182–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Fang EF, Hou Y, Palikaras K, Adriaanse BA, Kerr JS, Yang B, et al. Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci. 2019;22:401–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Lutz AK, Exner N, Fett ME, Schlehe JS, Kloos K, Lammermann K, et al. Loss of parkin or PINK1 function increases Drp1-dependent mitochondrial fragmentation. J Biol Chem. 2009;284:22938–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Wang SH, Zhu XL, Wang F, Chen SX, Chen ZT, Qiu Q, et al. LncRNA H19 governs mitophagy and restores mitochondrial respiration in the heart through Pink1/Parkin signaling during obesity. Cell Death Dis. 2021;12:557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Wu H, Wang Y, Li W, Chen H, Du L, Liu D, et al. Deficiency of mitophagy receptor FUNDC1 impairs mitochondrial quality and aggravates dietary-induced obesity and metabolic syndrome. Autophagy. 2019;15:1882–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Ko MS, Yun JY, Baek IJ, Jang JE, Hwang JJ, Lee SE, et al. Mitophagy deficiency increases NLRP3 to induce brown fat dysfunction in mice. Autophagy. 2021;17:1205–21.

    Article  CAS  PubMed  Google Scholar 

  168. Stavoe AKH, Holzbaur ELF. Autophagy in Neurons. Annu Rev Cell Dev Biol. 2019;35:477–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr. 2011;93:884S–890S.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Lopez-Lluch G, Hunt N, Jones B, Zhu M, Jamieson H, Hilmer S, et al. Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci USA. 2006;103:1768–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Ventura-Clapier R, Garnier A, Veksler V. Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. Cardiovasc Res. 2008;79:208–17.

    Article  CAS  PubMed  Google Scholar 

  172. Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr. 2011;93:884S–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Burns LEJM, Swerdlow RH. Effect of high-intensity exercise on aged mouse brain mitochondria, neurogenesis, and inflammation. Neurobiol Aging. 2014;35:2574–83.

    Article  PubMed  PubMed Central  Google Scholar 

  174. Chen CL, Hsu SC, Chung TY, Chu CY, Wang HJ, Hsiao PW, et al. Arginine is an epigenetic regulator targeting TEAD4 to modulate OXPHOS in prostate cancer cells. Nat Commun. 2021;12:2398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Vina J, Gomez-Cabrera MC, Borras C, Froio T, Sanchis-Gomar F, Martinez-Bello VE, et al. Mitochondrial biogenesis in exercise and in ageing. Adv Drug Deliv Rev. 2009;61:1369–74.

    Article  CAS  PubMed  Google Scholar 

  176. Shaerzadeh F, Motamedi F, Minai-Tehrani D, Khodagholi F. Monitoring of neuronal loss in the hippocampus of Abeta-injected rat: autophagy, mitophagy, and mitochondrial biogenesis stand against apoptosis. Neuromol Med. 2014;16:175–90.

    Article  CAS  Google Scholar 

  177. Shaerzadeh F, Motamedi F, Khodagholi F. Inhibition of akt phosphorylation diminishes mitochondrial biogenesis regulators, tricarboxylic acid cycle activity and exacerbates recognition memory deficit in rat model of Alzheimer’s disease. Cell Mol Neurobiol. 2014;34:1223–33.

    Article  CAS  PubMed  Google Scholar 

  178. Fanibunda SE, Deb S, Maniyadath B, Tiwari P, Ghai U, Gupta S, et al. Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1-PGC-1alpha axis. Proc Natl Acad Sci USA. 2019;116:11028–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Kang EB, Koo JH, Jang YC, Yang CH, Lee Y, Cosio-Lima LM, et al. Neuroprotective effects of endurance exercise against high-fat diet-induced hippocampal neuroinflammation. J Neuroendocrinol. 2016;28:1–10.

  180. Jeong JH, Kang EB. Effects of treadmill exercise on PI3K/AKT/GSK-3beta pathway and tau protein in high-fat diet-fed rats,. J Exerc Nutr Biochem. 2018;22:9–14.

    Article  Google Scholar 

  181. Jeong JH, Koo JH, Cho JY, Kang EB. Neuroprotective effect of treadmill exercise against blunted brain insulin signaling, NADPH oxidase, and Tau hyperphosphorylation in rats fed a high-fat diet. Brain Res Bull. 2018;142:374–83.

    Article  CAS  PubMed  Google Scholar 

  182. Navarro A, Gomez C, López-Cepero JM, Boveris A. Beneficial effects of moderate exercise on mice aging_ survival, behavior, oxidative stress, and mitochondrial electron transfer. Am J Physiol-Regul Integr Comp Physiol. 2004;286:R505–R511.

    Article  CAS  PubMed  Google Scholar 

  183. Takimoto M, Hamada T. Acute exercise increases brain region-specific expression of MCT1, MCT2, MCT4, GLUT1, and COX IV proteins. J Appl Physiol. 2014;116:1238–50.

    Article  CAS  PubMed  Google Scholar 

  184. Boveris A, Navarro A. Systemic and mitochondrial adaptive responses to moderate exercise in rodents. Free Rad Biol Med. 2008;44:224–9.

    Article  CAS  PubMed  Google Scholar 

  185. Navarro A. Mitochondrial enzyme activities as biochemical markers of aging. Mol. Aspects Med. 2004;25:37–48.

    Article  CAS  PubMed  Google Scholar 

  186. Freitas DA, Rocha-Vieira E, Soares BA, Nonato LF, Fonseca SR, Martins JB, et al. High intensity interval training modulates hippocampal oxidative stress, BDNF and inflammatory mediators in rats. Physiol Behav. 2018;184:6–11.

    Article  CAS  PubMed  Google Scholar 

  187. Vieira JM, Carvalho FB, Gutierres JM, Soares MSP, Oliveira PS, Rubin MA, et al. Caffeine prevents high-intensity exercise-induced increase in enzymatic antioxidant and Na+-K+-ATPase activities and reduction of anxiolytic like-behaviour in rats. Redox Report. 2017;22:493–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Feter N, Spanevello RM, Soares MSP, Spohr L, Pedra NS, Bona NP, et al. How does physical activity and different models of exercise training affect oxidative parameters and memory? Physiol Behav. 2019;201:42–52.

    Article  CAS  PubMed  Google Scholar 

  189. Melo CS, Rocha-Vieira E, Freitas DA, Soares BA, Rocha-Gomes A, Riul TR, et al. A single session of high-intensity interval exercise increases antioxidants defenses in the hippocampus of Wistar rats. Physiol Behav. 2019;211:112675.

    Article  CAS  PubMed  Google Scholar 

  190. Marques Neto SR, Castiglione RC, da Silva TCB, Paes LDS, Pontes A, Oliveira DF, et al. Effects of high intensity interval training on neuro-cardiovascular dynamic changes and mitochondrial dysfunction induced by high-fat diet in rats. PloS ONE. 2020;15:e0240060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Jaroslawska J, Gospodarska E, Korytko A. Increasing energy expenditure through exercise and low ambient temperature offers oxidative protection to the hypothalamus after high-fat feeding to mice. J Neuroendocrinol. 2022;34:e13095.

    Article  CAS  PubMed  Google Scholar 

  192. de Sousa Fernandes MS, Aidar FJ, da Silva Pedroza AA, de Andrade Silva SC, Santos GCJ, Dos Santos Henrique R, et al. Effects of aerobic exercise training in oxidative metabolism and mitochondrial biogenesis markers on prefrontal cortex in obese mice. BMC Sports Sci Med Rehabil. 2022;14:213.

    Article  PubMed  PubMed Central  Google Scholar 

  193. Gusdon AM, Callio J, Distefano G, O’Doherty RM, Goodpaster BH, Coen PM, et al. Exercise increases mitochondrial complex I activity and DRP1 expression in the brains of aged mice. Exp Gerontol. 2017;90:1–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Marques-Aleixo I, Santos-Alves E, Balca MM, Rizo-Roca D, Moreira PI, Oliveira PJ, et al. Physical exercise improves brain cortex and cerebellum mitochondrial bioenergetics and alters apoptotic, dynamic and auto(mito)phagy markers. Neuroscience. 2015;301:480–95.

    Article  CAS  PubMed  Google Scholar 

  195. Steiner JL, Murphy EA, Mcclellan JL, et al. training increases mitochondrial biogenesis in the brain. J Appl Physiol. 2011;111:1066–71.

    Article  CAS  PubMed  Google Scholar 

  196. Li B, Liang F, Ding X, Yan Q, Zhao Y, Zhang X, et al. Interval and continuous exercise overcome memory deficits related to beta-Amyloid accumulation through modulating mitochondrial dynamics. Behav Brain Res. 2019;376:112171.

    Article  PubMed  Google Scholar 

  197. Hu J, Cai M, Shang Q, Li Z, Feng Y, Liu B, et al. Elevated lactate by high-intensity interval training regulates the hippocampal bdnf expression and the mitochondrial quality control system. Front Physiol. 2021;12:629914.

    Article  PubMed  PubMed Central  Google Scholar 

  198. Lu LEJ, Burns JM, Swerdlow RH. Effect of exercise on mouse liver and brain bioenergetic infrastructures. Exp Physiol. 2013;98:207–19.

    Article  PubMed  Google Scholar 

  199. Kwon I, Jang Y, Lee Y. Endurance exercise-induced autophagy/mitophagy coincides with a reinforced anabolic state and increased mitochondrial turnover in the cortex of young male mouse brain. J Mol Neurosci: MN. 2021;71:42–54.

    Article  CAS  PubMed  Google Scholar 

  200. Lu LEJ, Selfridge JE, Burns JM, Swerdlow RH. Lactate administration reproduces specific brain and liver exercise-related changes. J Neurochem. 2013;127:91–100.

    Article  PubMed  PubMed Central  Google Scholar 

  201. Luo L, Dai JR, Guo SS, Lu AM, Gao XF, Gu YR, et al. Lysosomal proteolysis is associated with exercise-induced improvement of mitochondrial quality control in aged hippocampus. J Gerontol Series A, Biol Sci Med Sci. 2017;72:1342–51.

    Article  CAS  Google Scholar 

  202. Zhang Q, Wu Y, Sha H, Zhang P, Jia J, Hu Y, et al. Early exercise affects mitochondrial transcription factors expression after cerebral ischemia in rats. Int J Mol Sci. 2012;13:1670–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Zhang Q, Wu Y, Zhang P, Sha H, Jia J, Hu Y, et al. Exercise induces mitochondrial biogenesis after brain ischemia in rats. Neuroscience. 2012;205:10–7.

    Article  CAS  PubMed  Google Scholar 

  204. Lourenco MV, Frozza RL, de Freitas GB, Zhang H, Kincheski GC, Ribeiro FC, et al. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nat Med. 2019;25:165–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, et al. Exercise induces hippocampal BDNF through a PGC-1alpha/FNDC5 pathway. Cell Metab. 2013;18:649–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Tu T, Yin S, Pang J, Zhang X, Zhang L, Zhang Y, et al. Irisin contributes to neuroprotection by promoting mitochondrial biogenesis after experimental subarachnoid hemorrhage. Front Aging Neurosci. 2021;13:640215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. El Hayek L, Khalifeh M, Zibara V, Abi Assaad R, Emmanuel N, Karnib N, et al. Lactate mediates the effects of exercise on learning and memory through SIRT1-dependent activation of hippocampal brain-derived neurotrophic factor (BDNF). J Neurosci: Off J Soc Neurosci. 2019;39:2369–82.

    Google Scholar 

  208. Hashimoto T, Hussien R, Oommen S, Gohil K, Brooks GA. Lactate sensitive transcription factor network in L6 cells: activation of MCT1 and mitochondrial biogenesis. FASEB J: Off Publ Feder Am Soc Exp Biol. 2007;21:2602–12.

    Article  CAS  Google Scholar 

  209. W.H. Organization, WHO Guidelines on Physical Activity and Sedentary Behaviour, 2020. https://www.who.int/publications/i/item/9789240015128.

  210. Li Y, Xia X, Yu A, Xu H, Zhang C. Duration of an acute moderate-intensity exercise session affects approach bias toward high-calorie food among individuals with obesity. Appetite. 2022;172:105955.

    Article  PubMed  Google Scholar 

  211. Hansen D, Niebauer J, Cornelissen V, Barna O, Neunhauserer D, Stettler C, et al. Exercise prescription in patients with different combinations of cardiovascular disease risk factors: a consensus statement from the EXPERT working group. Sports Med. 2018;48:1781–97.

    Article  PubMed  Google Scholar 

  212. Su L, Fu J, Sun S, Zhao G, Cheng W, Dou C, et al. Effects of HIIT and MICT on cardiovascular risk factors in adults with overweight and/or obesity: a meta-analysis. PloS ONE. 2019;14:e0210644.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Hu J, Liu M, Yang R, Wang L, Liang L, Yang Y, et al. Effects of high-intensity interval training on improving arterial stiffness in Chinese female university students with normal weight obese: a pilot randomized controlled trial. J Transl Med. 2022;20:60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. De Sousa RAL, Santos LG, Lopes PM, Cavalcante BRR, Improta-Caria AC, Cassilhas RC. Physical exercise consequences on memory in obesity: a systematic review. Obes Rev: Off J Int Assoc Study Obes. 2021;22:e13298.

    Article  Google Scholar 

  215. Hillman CH, Erickson KI, Kramer AF. Be smart, exercise your heart: exercise effects on brain and cognition. Nat Rev Neurosci. 2008;9:58–65.

    Article  CAS  PubMed  Google Scholar 

  216. Cadenas-Sanchez C, Mora-Gonzalez J, Migueles JH, Martin-Matillas M, Gomez-Vida J, Escolano-Margarit MV, et al. An exercise-based randomized controlled trial on brain, cognition, physical health and mental health in overweight/obese children (ActiveBrains project): Rationale, design and methods. Contemp Clin Trials. 2016;47:315–24.

    Article  PubMed  Google Scholar 

  217. Wheeler MJ, Green DJ, Ellis KA, Cerin E, Heinonen I, Naylor LH, et al. Distinct effects of acute exercise and breaks in sitting on working memory and executive function in older adults: a three-arm, randomised cross-over trial to evaluate the effects of exercise with and without breaks in sitting on cognition. Br J Sports Med. 2020;54:776–81.

    Article  PubMed  Google Scholar 

  218. Strassnig MT, Signorile JF, Potiaumpai M, Romero MA, Gonzalez C, Czaja S, et al. High velocity circuit resistance training improves cognition, psychiatric symptoms and neuromuscular performance in overweight outpatients with severe mental illness. Psychiatry Res. 2015;229:295–301.

    Article  PubMed  Google Scholar 

  219. Russo A, Buratta L, Pippi R, Aiello C, Ranucci C, Reginato E, et al. Effect of training exercise on urinary brain-derived neurotrophic factor levels and cognitive performances in overweight and obese subjects. Psychol Rep. 2017;120:70–87.

    Article  PubMed  Google Scholar 

  220. Drigny J, Gremeaux V, Dupuy O, Gayda M, Bherer L, Juneau M, et al. Effect of interval training on cognitive functioning and cerebral oxygenation in obese patients: a pilot study. J Rehab Med. 2014;46:1050–4.

    Article  Google Scholar 

  221. Zlibinaite L, Solianik R, Vizbaraite D, Mickeviciene D, Skurvydas A. The effect of combined aerobic exercise and calorie restriction on mood, cognition, and motor behavior in overweight and obese women. J Phys Activity Health. 2020;17:204–10.

    Article  Google Scholar 

  222. Ortega FB, Mora-Gonzalez J, Cadenas-Sanchez C, Esteban-Cornejo I, Migueles JH, Solis-Urra P, et al. Effects of an exercise program on brain health outcomes for children with overweight or obesity: the activebrains randomized clinical trial. JAMA Netw Open. 2022;5:e2227893.

    Article  PubMed  PubMed Central  Google Scholar 

  223. Martin A, Booth JN, Laird Y, Sproule J, Reilly JJ, Saunders DH. Physical activity, diet and other behavioural interventions for improving cognition and school achievement in children and adolescents with obesity or overweight. Cochrane Database Syst Rev. 2018;3:CD009728.

    PubMed  Google Scholar 

  224. Mora-Gonzalez J, Esteban-Cornejo I, Cadenas-Sanchez C, Migueles JH, Rodriguez-Ayllon M, Molina-Garcia P, et al. Fitness, physical activity, working memory, and neuroelectric activity in children with overweight/obesity. Scand J Med Sci Sports. 2019;29:1352–63.

    Article  PubMed  Google Scholar 

Download references

Funding

This work was sponsored by Shanghai Sailing Program (22YF1441600), the grant of the funding of Youth Fund Project of Research Planning Foundation on Humanities and Social Sciences of the Ministry of Education (20YJCZH001), the Scientific Research Foundation of SUMHS (SSF-21-03-008), the Project of Key Medical Discipline Group Construction in Shanghai Pudong New Area (No. PWZxq2022-13) and the Project of Clinical Outstanding Discipline Construction in Shanghai Pudong New Area (No. PWYgy2021-09).

Author information

Authors and Affiliations

Authors

Contributions

Ming Cai, Jian Wan, and Kenren Cai is the co-first authors. They drafted the manuscript and contributed equally to this article. Shuyao Li, Xinlin Du, and Haihan Song assisted with drafting the tables and figures. Wanju Sun and Jingyun Hu conceptualized the article and revised the final version. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Wanju Sun or Jingyun Hu.

Ethics declarations

Competing interests

The authors declare no competing of interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cai, M., Wan, J., Cai, K. et al. The mitochondrial quality control system: a new target for exercise therapeutic intervention in the treatment of brain insulin resistance-induced neurodegeneration in obesity. Int J Obes 48, 749–763 (2024). https://doi.org/10.1038/s41366-024-01490-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-024-01490-x

Search

Quick links